chr9-104794495-T-G

Variant names:

• chr9-104794495-T-G
• rs146292819
• NM_005502.4:c.5398A>C

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 10P and 1B. PP3_Moderate PP5_Very_Strong BS2_Supporting

The NM_005502.4(ABCA1):​c.5398A>C​(p.Asn1800His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000355 in 1,588,820 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. N1800N) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00038 (0 hom., cov: 29)
  • Exomes 𝑓: 0.00035 (2 hom.)
• Consequence: ABCA1 NM_005502.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:12
• Conservation: PhyloP100: 8.01
• Publications: 49 publications found

Genes affected

ABCA1 (HGNC:29): (ATP binding cassette subfamily A member 1) The membrane-associated protein encoded by this gene is a member of the superfamily of ATP-binding cassette (ABC) transporters. ABC proteins transport various molecules across extra- and intracellular membranes. ABC genes are divided into seven distinct subfamilies (ABC1, MDR/TAP, MRP, ALD, OABP, GCN20, White). This protein is a member of the ABC1 subfamily. Members of the ABC1 subfamily comprise the only major ABC subfamily found exclusively in multicellular eukaryotes. With cholesterol as its substrate, this protein functions as a cholesteral efflux pump in the cellular lipid removal pathway. Mutations in both alleles of this gene cause Tangier disease and familial high-density lipoprotein (HDL) deficiency. [provided by RefSeq, Sep 2019]

ABCA1 Gene-Disease associations (from GenCC):

• hypoalphalipoproteinemia, primary, 1

  Inheritance: AD Classification: DEFINITIVE, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• Tangier disease

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Orphanet
• apolipoprotein A-I deficiency

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.933
• PP5: Variant 9-104794495-T-G is Pathogenic according to our data. Variant chr9-104794495-T-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 364389.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAdExome4 at 2 AD,AR geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005502.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCA1	NM_005502.4	MANE Select	c.5398A>C	p.Asn1800His	missense	Exon 40 of 50	NP_005493.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCA1	ENST00000374736.8	TSL:1 MANE Select	c.5398A>C	p.Asn1800His	missense	Exon 40 of 50	ENSP00000363868.3
	ABCA1	ENST00000678995.1		c.5404A>C	p.Asn1802His	missense	Exon 40 of 50	ENSP00000504612.1

Frequencies

GnomAD3 genomes AF: 0.000382 AC: 52 AN: 136238 Hom.: 0 Cov.: 29

Gnomad AFR AF: 0.000110

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000317

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000242

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000652

Gnomad OTH AF: 0.000581

GnomAD2 exomes AF: 0.000286 AC: 69 AN: 240978 AF XY: 0.000330

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000181

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000568

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000352 AC: 512 AN: 1452582 Hom.: 2 Cov.: 42 AF XY: 0.000338 AC XY: 244 AN XY: 722898

African (AFR) AF: 0.00 AC: 0 AN: 33292

American (AMR) AF: 0.000250 AC: 11 AN: 43996

Ashkenazi Jewish (ASJ) AF: 0.0000387 AC: 1 AN: 25868

East Asian (EAS) AF: 0.00 AC: 0 AN: 39578

South Asian (SAS) AF: 0.000105 AC: 9 AN: 85772

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51820

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5718

European-Non Finnish (NFE) AF: 0.000425 AC: 470 AN: 1106560

Other (OTH) AF: 0.000350 AC: 21 AN: 59978

GnomAD4 genome AF: 0.000382 AC: 52 AN: 136238 Hom.: 0 Cov.: 29 AF XY: 0.000429 AC XY: 28 AN XY: 65324

African (AFR) AF: 0.000110 AC: 4 AN: 36208

American (AMR) AF: 0.000317 AC: 4 AN: 12610

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3378

East Asian (EAS) AF: 0.00 AC: 0 AN: 4696

South Asian (SAS) AF: 0.000242 AC: 1 AN: 4138

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 7884

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.000652 AC: 42 AN: 64460

Other (OTH) AF: 0.000581 AC: 1 AN: 1720

Alfa AF: 0.000443 Hom.: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000930 AC: 8

ExAC AF: 0.000272 AC: 33

EpiCase AF: 0.000273

EpiControl AF: 0.000534

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:4

Feb 15, 2021

Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PS3, PP3, PM2

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces asparagine, which is neutral and polar, with histidine, which is basic and polar, at codon 1800 of the ABCA1 protein (p.Asn1800His). This variant is present in population databases (rs146292819, gnomAD 0.06%). This missense change has been observed in individuals with Tangier disease or familial HDL deficiency (PMID: 10706591, 16343503, 20880529, 21575609, 22959828). This variant is also known as nt5338A>C, Asn1740His. ClinVar contains an entry for this variant (Variation ID: 364389). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt ABCA1 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects ABCA1 function (PMID: 16873719). For these reasons, this variant has been classified as Pathogenic.

Oct 29, 2020

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jul 22, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate impaired function of ABCA1, including significantly reducing ApoA-I binding and efflux of choline and cholesterol (PMID: 16873719, 17303779); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as p.(N1740H); This variant is associated with the following publications: (PMID: 35460704, 36411388, 34363016, 34662886, 16873719, 31980526, 28634189, 29083407, 28870971, 26073400, 26079414, 18523221, 21575609, 31589614, 32041611, 15297675, 7945562, 20533173, 20800056, 21130455, 21420943, 10706591, 15019541, 20880529, 23770607, 17303779, 22959828)

Hypoalphalipoproteinemia, primary, 1 Pathogenic:3

Jul 04, 2022

MGZ Medical Genetics Center

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Sep 12, 2019

Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This c.5398A>C (p.Asn1800His) variant is known to have a significant impact on ABCA1 function. In-vitro functional studies suggest it prevents the migration of the resultant protein to the plasma membrane, reducing the ability to efflux lipids and generate HDL cholesterol (PMID: 16873719). In the homozygous and heterozygous state, individuals with this variant had 3.4% and 56.6% of normal plasma HDL levels, respectively (PMID: 16873719, 16704350). This variant's allele frequency is 0.0006449 in the European (non-Finnish) population in gnomAD. The Asn1800 amino acid is highly conserved across species. Multiple computational tools suggest it has a deleterious effect on the gene product. This c.5398A>C (p.Asn1800His) variant in ABCA1 is therefore considered likely pathogenic.

Nov 14, 2022

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

ABCA1-related disorder Pathogenic:2

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Across a selection of the available literature, the ABCA1 c.5398A>C (p.Asn1800His) variant has been identified in a total of seven individuals with ABCA1-related dyslipidemias, including in a homozygous state in one patient, in a compound heterozygous state in three patients, and in a heterozygous state in three patients (Serfaty-Lacrosniere et al. 1994; Brousseau et al. 2000; Pisciotta et al. 2004; Kiss et al. 2007; Candini et al. 2010; Sorrenson et al. 2011; Morrison et al. 2013). Frikke-Schmidt et al. (2010) stated that the p.Asn1800His variant accounted for the majority of HDL lowering variants in the Copenhagen City Heart Study and the Copenhagen General Population Study, being present in 22 and 70 heterozygotes, respectively. Control data are unavailable for this variant, which is reported at a frequency of 0.00047 in the European (non-Finnish) population of the Exome Aggregation Consortium. Brunham et al. (2006) reviewed HDL levels in 33 heterozygotes for the p.Asn1800His variant, and found that HDL levels in these cases were 56.5 percent of those in age and gender-matched controls. Frikke-Schmidt et al. (2008) found that unadjusted plasma levels of HDL cholesterol in the 22 individuals from the Copenhagen City Heart Study with the p.Asn1800His variant were reduced by 16 mg/dL when compared to controls (P<.001). Singaraja et al. (2006) demonstrated that the p.Asn1800His variant results in a defective ABCA1 protein that fails to localize to the plasma membrane and accumulates intracellularly. Based on the collective evidence, the p.Asn1800His variant is classified as pathogenic for ABCA1-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.

Sep 02, 2023

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The ABCA1 c.5398A>C variant is predicted to result in the amino acid substitution p.Asn1800His. This variant has been reported in multiple patients with familial HDL deficiency or patients with Tangier disease (see for example, Table 1, Berge and Leren. 2010. PubMed ID: 20800056; Table 1, Fasano et al. 2012. PubMed ID: 22959828; Table 1, Candini et al. 2010. PubMed ID: 20880529). This variant has also been shown to segregate with HDL deficiency in multiple families (Figure 2B, Alrasadi et al. 2005. PubMed ID: 16343503; Figure 1, Pisciotta et al. 2004. PubMed ID: 15019541). An in vitro experimental study suggests this variant affects protein localization leading to intracellular accumulation (Figure 2, Singaraja et al. 2006. PubMed ID: 16873719). This variant is reported in 0.064% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/9-107556776-T-G). This variant is interpreted as pathogenic.

Decreased HDL cholesterol concentration Pathogenic:1

Dec 23, 2022

Molecular Genetics, Royal Melbourne Hospital

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change in ABCA1 is predicted to replace asparagine with histidine at codon 1800, p.(Asn1800His). The asparagine residue is highly conserved (98/99 vertebrates, UCSC), and is located in a transmembrane domain. There is a moderate physicochemical difference between asparagine and histidine. The highest population minor allele frequency in the population database gnomAD v2.1 is 0.06% (79/122,504 alleles) in the European (non-Finnish) population. The variant in the heterozygous state is significantly associated with low high-density lipoprotein cholesterol (HDL-C) lipid levels with no overt clinical manifestations (PMID: 29083407). This variant has been detected in at least five individuals with HDL-C deficiency and segregates in a single family. Of those individuals, one individual was homozygous and two were compound heterozygous for the variant and a pathogenic variant. The homozygous individual was the only proband with a clinical diagnosis of Tangier disease (PMID: 10706591, 15019541, 16343503, 20880529). At least one individual with this variant displayed impaired cellular cholesterol efflux, which is highly specific for ABCA1-related HDL-C deficiency (PMID: 10706591, 16343503). Furthermore, in vitro cellular cholesterol efflux assays, showed impaired cholesterol efflux indicating that this variant impacts protein function (PMID: 16873719, 17303779, 18523221). Multiple lines of computational evidence predict a deleterious effect for the missense substitution (6/6 algorithms). Based on the classification scheme RMH Modified ACMG Guidelines v1.5.1, this variant is classified as LIKELY PATHOGENIC. Following criteria are met: PM3_Strong, PS3_Supporting, PP1, PP3, PP4.

Familial hypoalphalipoproteinemia Pathogenic:1

May 02, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: ABCA1 c.5398A>C (p.Asn1800His) results in a conservative amino acid change located in the ABC-2 type transporter, transmembrane domain (IPR013525) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00029 in 240978 control chromosomes, predominantly at a frequency of 0.00057 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 57-fold of the estimated maximal expected allele frequency for a pathogenic variant in ABCA1 causing Familial Hypoalphalipoproteinemia phenotype (1e-05). However, c.5398A>C has been reported in the literature in multiple individuals affected with Familial Hypoalphalipoproteinemia, including one homozygote (Brousseau_2000), compound heterozygotes (e.g. Pisciotta_2004, Alrasadi_2006, Candini_2010) and several heterozygotes (e.g. Alrasadi_2006, Berge_2010, Fasano_2012). These data indicate that the variant is very likely to be associated with disease. Publications report experimental evidence evaluating an impact on protein function. The variant protein resulted in a loss of cholesterol efflux activity and impaired localization at the plasma membrane (Singaraja_2006, Kiss_2007). The following publications have been ascertained in the context of this evaluation (PMID: 20880529, 16343503, 20800056, 10706591, 22959828, 15019541, 16873719, 17303779). ClinVar contains an entry for this variant (Variation ID: 364389). Based on the evidence outlined above, the variant was classified as likely pathogenic.

Cardiovascular phenotype Pathogenic:1

Jul 23, 2025

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.N1800H variant (also known as c.5398A>C), located in coding exon 39 of the ABCA1 gene, results from an A to C substitution at nucleotide position 5398. The asparagine at codon 1800 is replaced by histidine, an amino acid with similar properties. This variant has been detected in the homozygous state in an individual reported to have Tangier disease, and has been reported to segregate with low HDL cholesterol in related heterozygotes (Serfaty-Lacrosniere C et al. Atherosclerosis, 1994 May;107:85-98; Brousseau ME et al. J. Lipid Res., 2000 Mar;41:433-41 (reported as p.Asp1740His); Singaraja RR et al. Circ. Res., 2006 Aug;99:389-97; Pisciotta L et al. Atherosclerosis. 2004 Feb;172(2):309-20). This variant has been reported to co-occur with other ABCA1 variants in individuals with extremely low HDL levels, however phase was not confirmed (Candini C et al. Atherosclerosis, 2010 Dec;213:492-8; Sorrenson B et al. Biochem. Biophys. Res. Commun., 2011 Jun;409:400-5). This variant has also been reported in association with significant HDL reduction in heterozygous carriers in a population-based study, and in additional cohorts with low HDL (Alrasadi K et al. Atherosclerosis. 2006 Oct;188(2):281-91; Frikke-Schmidt R et al. JAMA, 2008 Jun;299:2524-32; Bochem AE et al. Eur. Heart J., 2013 Jan;34:286-91; Morrison AC et al. Nat. Genet., 2013 Aug;45:899-901; Dron JS et al. J. Lipid Res., 2017 11;58:2162-2170). In addition, several in vitro studies of patient and transfected cells exhibiting this variant demonstrated reduced cholesterol efflux (Singaraja RR et al. Circ. Res., 2006 Aug;99:389-97; Kiss RS et al. Arterioscler. Thromb. Vasc. Biol., 2007 May;27:1139-45; Frikke-Schmidt R et al. JAMA, 2008 Jun;299:2524-32; Sorrenson B et al. Biochem. Biophys. Res. Commun., 2011 Jun;409:400-5; Fasano T et al. Mol. Genet. Metab., 2012 Nov;107:534-41). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the majority of available evidence to date, this variant is likely to be pathogenic.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.52
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Uncertain	-0.020
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.75	D
Eigen	Pathogenic	0.73
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.83	T
M_CAP	Uncertain	0.24	D
MetaRNN	Pathogenic	0.93	D
MetaSVM	Uncertain	0.66	D
MutationAssessor	Pathogenic	2.9	M
PhyloP100		8.0
PrimateAI	Pathogenic	0.82	D
PROVEAN	Uncertain	-3.8	D
REVEL	Pathogenic	0.88
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0050	D
Polyphen		0.87	P
Vest4		0.94
MVP		0.95
MPC		0.84
ClinPred		0.56	D
GERP RS		5.5
Varity_R		0.80
gMVP		0.90
Mutation Taster		=56/44	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs146292819; hg19: chr9-107556776;